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The BLIMP1—EZH2 nexus in a non-Hodgkin lymphoma

Abstract

Waldenström’s macroglobulinemia (WM) is a non-Hodgkin lymphoma, resulting in antibody-secreting lymphoplasmacytic cells in the bone marrow and pathologies resulting from high levels of monoclonal immunoglobulin M (IgM) in the blood. Despite the key role for BLIMP1 in plasma cell maturation and antibody secretion, its potential effect on WM cell biology has not yet been explored. Here we provide evidence of a crucial role for BLIMP1 in the survival of cells from WM cell line models and further demonstrate that BLIMP1 is necessary for the expression of the histone methyltransferase EZH2 in both WM and multiple myeloma cell lines. The effect of BLIMP1 on EZH2 levels is post-translational, at least partially through the regulation of proteasomal targeting of EZH2. Chromatin immunoprecipitation analysis and transcriptome profiling suggest that the two factors co-operate in regulating genes involved in cancer cell immune evasion. Co-cultures of natural killer cells and cells from a WM cell line further suggest that both factors participate in immune evasion by promoting escape from natural killer cell-mediated cytotoxicity. Together, the interplay of BLIMP1 and EZH2 plays a vital role in promoting the survival of WM cell lines, suggesting a role for the two factors in Waldenström’s macroglobulinaemia.

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Fig. 1: BLIMP1 promotes the survival of WM cells.
Fig. 2: BLIMP1 maintains EZH2 protein levels in WM cells.
Fig. 3: BLIMP1 KD and EZH2 inhibition induce overlapping transcriptional changes.
Fig. 4: BLIMP1 binds at a distance to the H3K27me3 mark.
Fig. 5: BLIMP1 regulates a subset of target genes via EZH2.
Fig. 6: BLIMP1 and EZH2 promote WM tumour immune evasion.

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Data availability

RNAseq and ChIPseq data are available at http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-7739 under the accession code: E-MTAB-7739.

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Acknowledgements

We thank deCODE Genetics/Amgen for the high throughput sequencing, Arnar Pálsson and Dagný A. Rúnarsdóttir for their advice on RNAseq data analysis, Árni Ásbjarnarson for technical assistance on western blot analysis, Jóna Freysdóttir and Sunnefa Yeatman Ómarsdottir for their advice on the isolation of NK cells, and the group of Eirikur Steingrimsson for useful discussions and advice on the project. We thank Helga M. Ögmundsdóttir for advice and helpful discussions on the manuscript and we thank Dr. Roopsha Sengupta for providing critical inputs and proof-reading the manuscript.

Funding

This work was supported by project grants from the Icelandic Research Fund (grant no. 140950-051) and the Icelandic Cancer Society, a doctoral fellowship from the University of Iceland, and grant from the University of Iceland Eggertssjodur and funds from the COST Project EpiChemBio.

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Anderson, K.J., Ósvaldsdóttir, Á.B., Atzinger, B. et al. The BLIMP1—EZH2 nexus in a non-Hodgkin lymphoma. Oncogene 39, 5138–5151 (2020). https://doi.org/10.1038/s41388-020-1347-8

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